Sarigul Ozbek Sevgi, Bacak Erdik Melis, Dogan Ilknur
Faculty of Pharmacy, Acibadem Mehmet Ali Aydinlar University, Atasehir, Istanbul 34752, Turkey.
Department of Chemistry, Bogazici University, Bebek, Istanbul 34342, Turkey.
ACS Omega. 2021 Oct 15;6(42):27823-27832. doi: 10.1021/acsomega.1c03452. eCollection 2021 Oct 26.
Two novel axially chiral -trifluoromethylphenyl thiohydantoin derivatives have been prepared atroposelectively from the reaction of and alanine methyl ester HCl salts with -trifluoromethylphenyl isothiocyanate in the presence of triethyl amine. It was found that after purification of the crude product by simple recrystallization, the amino acid esters yielded thiohydantoins having solely axial chirality whereas the ones returned the isomers only. This result prompted us to perform sterically controlled aldol reactions on and thiohydantoin atropisomers. It was found that during the aldol reaction of 3--trifluoromethyl-5-methylthiohydantoins, the -trifluoromethyl group of the isomers efficiently shielded the face of the intermediate and in this way, enabled the selective formation of only the configured aldol products at C5 of the heterocyclic ring. The thiohydantoins, on the other hand, yielded only the C5 configured aldol products as a result of the face shielding of the -trifluoromethyl group of intermediate enolates. A noteworthy face selectivity of the benzaldehyde molecule was not observed ( only 3/2) during the aldolization of trifluoromethylphenyl derivatives of thiohydantoins. Aldol reactions were also done using the previously synthesized axially chiral thiohydantoins with -Cl, Br, and I phenyl substituents which had predominantly conformations (/ ratios > 95%), and the stereochemical outcomes were compared with those of the -trifluoromethyl substituted ones. 80-90% face selectivity of the benzaldehyde molecule was observed for the axially chiral -halophenyl substituted thiohydantoins. The syntheses done with axially chiral 3--trifluoromethylphenyl- and 3--iodophenyl-5-methyl thiohydantoins enabled stereoselective formation of quaternized chiral carbon centers at C5 of the thiohydantoin ring.
通过在三乙胺存在下，使缬氨酸甲酯盐酸盐和丙氨酸甲酯盐酸盐与三氟甲基苯基异硫氰酸酯反应，非对映选择性地制备了两种新型轴向手性三氟甲基苯基硫代乙内酰脲衍生物。发现通过简单重结晶纯化粗产物后，缬氨酸甲酯产生仅具有单一轴向手性的硫代乙内酰脲，而丙氨酸甲酯则仅得到其对映异构体。这一结果促使我们对L-和D-硫代乙内酰脲非对映异构体进行空间控制的羟醛反应。发现在3-三氟甲基-5-甲基硫代乙内酰脲的羟醛反应中，L-异构体的三氟甲基有效地屏蔽了中间体的Re面，从而使得在杂环的C5处仅选择性地形成S-构型的羟醛产物。另一方面，由于中间体烯醇盐的三氟甲基的Si面被屏蔽，D-硫代乙内酰脲仅产生R-C5构型的羟醛产物。在硫代乙内酰脲的三氟甲基苯基衍生物的羟醛缩合反应中，未观察到苯甲醛分子值得注意的面选择性（仅3/2）。还使用先前合成的具有主要为S-构象（S/R比率>95%）的-Cl、-Br和-I苯基取代基的轴向手性硫代乙内酰脲进行羟醛反应，并将立体化学结果与三氟甲基取代的硫代乙内酰脲的结果进行比较。对于轴向手性卤代苯基取代的硫代乙内酰脲，观察到苯甲醛分子80-90%的面选择性。用轴向手性3-三氟甲基苯基-和3-碘苯基-5-甲基硫代乙内酰脲进行的合成能够在硫代乙内酰脲环的C5处立体选择性地形成季铵化的手性碳中心。
